WO2010141545A1 - Bis-pyridylpyridones à usage d'antagonistes de récepteur d'hormone concentrant la mélanine 1 - Google Patents

Bis-pyridylpyridones à usage d'antagonistes de récepteur d'hormone concentrant la mélanine 1 Download PDF

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WO2010141545A1
WO2010141545A1 PCT/US2010/037017 US2010037017W WO2010141545A1 WO 2010141545 A1 WO2010141545 A1 WO 2010141545A1 US 2010037017 W US2010037017 W US 2010037017W WO 2010141545 A1 WO2010141545 A1 WO 2010141545A1
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compound
alkyl
pharmaceutically acceptable
cycloalkyl
oxo
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PCT/US2010/037017
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English (en)
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Siegfried Benjamin Christensen, Iv
Donghui Qin
Shuhui Chen
Shi LU
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Glaxosmithkline Llc
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Priority to EP10783986A priority Critical patent/EP2437601A4/fr
Priority to JP2012514068A priority patent/JP2012528872A/ja
Priority to US13/375,616 priority patent/US20120071459A1/en
Publication of WO2010141545A1 publication Critical patent/WO2010141545A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • This invention relates to novel bis-pyridylpyridones which are antagonists at the melanin-concentrating hormone receptor 1 (MCHR1 ), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy for the treatment of obesity and diabetes.
  • MCHR1 melanin-concentrating hormone receptor 1
  • Obesity is a medical condition that is reaching epidemic proportions among humans in a number of countries throughout the world. It is a condition that is also associated with or induces other diseases or conditions that disrupt life activities and lifestyles. Obesity is recognized as a serious risk factor for other diseases and conditions such as diabetes, hypertension, and arteriosclerosis. It is also known that increased body weight due to obesity can place a burden on joints, such as knee joints, causing arthritis, pain, and stiffness.
  • melanin-concentrating hormone originates in the hypothalamus and has orexigenic action (see Nature, Vol. 396, p. 670 (1998), for example. There is an ongoing need for the development of a melanin-concentrating hormone antagonist useful in the treatment of obesity and other associated or related diseases and conditions.
  • the present invention provides a compound of Formula (I),
  • R 1 is a saturated 6-12 membered heterocyclic ring system containing 1 or 2 ring nitrogen atoms and an optional ring oxygen atom, which ring system incorporates spiro rings and which is attached to the pyridine ring via a nitrogen atom;
  • R 2 is selected from the group consisting of: hydrogen, Ci -6 alkyl, -C(O)NR a R b , - C(O)R 3 , -SO 2 R 3 , -C(O)OR 3 , oxo, -C(0)NR 3 R b , -NR 3 R b , -NR 3 C(0)R b , -NR 3 C(0)0R b , and - NR 3 SO 2 R";
  • R 3 is selected from the group consisting of: hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl
  • R b is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, aryl, and heteroaryl; or R 3 and R b together with the nitrogen to which they are attached form a heterocycloalkyl, and said heterocycloalkyl is optionally substituted with one, two, or three R c groups;
  • R 3 is H, F, Cl, C 1-3 alkyl, cyclopropyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, oxo, or CN;
  • R c is H, F, Cl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, oxo, or CN;
  • X is (CH 2 ) m ;
  • composition comprising a compound of Formula I or pharmaceutically acceptable salt thereof. Further, there is provided a pharmaceutical composition comprising a compound of
  • a method of treatment comprising the administering to a mammal, particularly a human, a pharmaceutical composition comprising a compound of Formula I or pharmaceutically acceptable salt thereof and at least one excipient, wherein said treatment is for obesity, diabetes, depression, or anxiety.
  • a compound of Formula I or pharmaceutically acceptable salt thereof for use in the treatment of obesity, diabetes, depression, or anxiety in a mammal, especially a human.
  • a process for preparing a compound of Formula I or pharmaceutically acceptable salt thereof is also provided.
  • the present invention relates to compounds of Formula I as shown above.
  • the present invention also relates to a compound of Formula (I)(A)
  • R1 is a saturated 6-12 membered heterocyclic ring system containing 1 or 2 ring nitrogen atoms and an optional ring oxygen atom, which ring system incorporates spiro rings and which is attached to the pyridine ring via a nitrogen atom;
  • R2 is selected from the group consisting of: hydrogen, Ci -6 alkyl, -C(O)N R a R b , - C(O)R 3 , -SO 2 R 3 , -C(O)OR 3 , oxo, -C(0)NR 3 R b , -NR 3 R b , -NR 3 C(0)R b , -NR 3 C(0)0R b , and - NR 3 SO 2 R";
  • R 3 is selected from the group consisting of: hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • R b is selected from the group consisting of: hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl; or R 3 and R b together with the nitrogen to which they are attached form a heterocycloalkyl, and said heterocycloalkyl is optionally substituted with one, two, or three R c groups;
  • R 3 is H, F, Cl, C 1-3 alkyl, cyclopropyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, oxo, or CN;
  • R c is H, F, Cl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, oxo, or CN;
  • X is (CH 2 ) m ; m is 0-2; n is 0-3; p is 0-3; with the proviso that R 2 is not -NR 3 COOH Or-NR 3 SO 2 H.
  • the present invention also relates to a compound of Formula (I)(B)
  • R1 is a saturated 6-12 membered heterocyclic ring system containing 1 or 2 ring nitrogen atoms and an optional ring oxygen atom, which ring system incorporates spiro rings and which is attached to the pyridine ring via a nitrogen atom;
  • R2 is selected from the group consisting of: hydrogen, Ci -6 alkyl, -C(O)N R a R b , - C(O)R 3 , -SO 2 R 3 , -C(O)OR 3 , oxo, -C(0)NR 3 R b , -NR 3 R b , -NR 3 C(0)R b , -NR 3 C(0)0R b , and - NR 3 SO 2 R';
  • R 3 is selected from the group consisting of: hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • R b is selected from the group consisting of: hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl; or R 3 and R b together with the nitrogen to which they are attached form a heterocycloalkyl, and said heterocycloalkyl is optionally substituted with one, two, or three R c groups;
  • R 3 is H, F, Cl, C 1-3 alkyl, cyclopropyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, oxo, or CN;
  • R c is H, F, Cl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, oxo, or CN;
  • X is (CH 2 ) m ; m is 0-2; n is 0-3; p is 0-3; with the proviso that R 2 is not -NR 3 COOH Or-NR 3 SO 2 H.
  • the present invention also relates to a compound of Formula (I)(C)
  • R1 is a saturated 6-12 membered heterocyclic ring system containing 1 or 2 ring nitrogen atoms and an optional ring oxygen atom, which ring system incorporates spiro rings and which is attached to the pyridine ring via a nitrogen atom;
  • R2 is selected from the group consisting of: hydrogen, C 1-6 alkyl, -C(O)N R a R b , - C(O)R 3 , -SO 2 R 3 , -C(O)OR 3 , oxo, -C(0)NR 3 R b , -NR 3 R b , -NR 3 C(0)R b , -NR 3 C(0)0R b , and - NR 3 SO 2 R';
  • R 3 is selected from the group consisting of: hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl;
  • R b is selected from the group consisting of: hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl; or R 3 and R b together with the nitrogen to which they are attached form a heterocycloalkyl, and said heterocycloalkyl is optionally substituted with one, two, or three R c groups;
  • R 3 is H, F, Cl, C 1-3 alkyl, cyclopropyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, oxo, or CN;
  • R c is H, F, Cl, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, oxo, or CN;
  • X is (CH 2 ) m ; m is 0-2; n is 0-3; p is 0-3; with the proviso that R 2 is not -NR 3 COOH or -N R 3 SO 2 H.
  • Preferred compounds of the present invention are compounds of Formula (I)(A), (I)(B) or (I)(C), wherein said said R1 is selected from: 1-oxo-2,7-diazaspiro[4.5]decan-7-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 1 ,7-diazaspiro[4.5]decan-7-yl, 1 ,7-diazaspiro[4.4]nonan-7-yl, 1 ,8-diazaspiro[5.5]undecan-8-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.5]nonan-2- yl, 1-0X0-2, 7-diazaspiro[3.5]nonan-7-yl, 7-methylamino-5-azaspiro[2.4]heptan-5-yl, 2,8- diazaspiro[4.5]decan-8-yl
  • Preferred compounds of the invention are compounds of Formula (I)(A) wherein R 3 is F or Cl, R b is selected from the group consisting of: hydrogen, C 1-6 alkyl, and C 3-6 cycloalkyl; m is 1 ; and n is 1.
  • the compound of the present invention may also be utilized in the form of a pharmaceutically acceptable salt thereof.
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
  • Salts of the compounds of the present invention may comprise acid addition salts. In general, the salts are formed from pharmaceutically acceptable inorganic and organic acids.
  • suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.
  • salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate
  • salts which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.
  • These salts such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.
  • the compound of Formula I or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • the individual stereoisomers may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms).
  • the present invention also includes the individual isomers of the compound or salt represented by the Formula I as well as mixtures with isomers thereof in which one or more chiral centers are inverted. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove.
  • alkyl refers to a straight or branched chain alkyl, preferably having from one to twelve carbon atoms, which may be unsubstituted or substituted, saturated or unsaturated with multiple degrees of substitution included within the present invention. Suitable substituents are selected from the group consisting of halogen, amino, substituted amino, cyano, hydroxyl, alkoxy and alkylthio.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, t-butyl, isopentyl, n-pentyl, and the like, as well as substituted versions thereof.
  • cycloalkyl refers to an unsubstituted or substituted mono- or polycyclic non-aromatic saturated ring, which optionally includes an alkylene linker through which the cycloalkyl may be attached.
  • exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as unsubstituted and substituted versions thereof.
  • alkoxy refers to the group -OR a , where R a is alkyl or cycloalkyl as defined above.
  • heterocycle or “heterocyclyl” refers to unsubstituted and substituted mono- or polycyclic non-aromatic ring system containing one or more heteroatoms.
  • Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
  • the ring is three to eight-membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution are included within the present definition.
  • heterocyclic groups include, but are not limited to tetrahydrofuranyl, pyranyl, 1 ,4-dioxanyl, 1 ,3-dioxanyl, piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, piperazinyl, pyrrolidinonyl, piperazinonyl, pyrazolidinyl, and their various tautomers.
  • aryl aromatic, hydrocarbon, ring system.
  • the ring system may be monocyclic or fused polycyclic (e.g., bicyclic, tricyclic, etc.), substituted or unsubstituted.
  • the monocyclic aryl ring is C5-C10, or C5-C7, or C5-C6, where these carbon numbers refer to the number of carbon atoms that form the ring system.
  • a C6 ring system i.e. a phenyl ring, is a suitable aryl group.
  • the polycyclic ring is a bicyclic aryl group, where suitable bicyclic aryl groups are C8-C12, or C9-C10.
  • a naphthyl ring, which has 10 carbon atoms, is a suitable polycyclic aryl group. Suitable substituents for aryl are described below in the definition of "optionally substituted".
  • heteroaryl an aromatic ring system containing carbon(s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junctions, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms).
  • heteroaryl groups include but are not limited to: benzofuran, benzothiophene, furan, imidazole, indole, isothiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, quinazoline, quinoxaline, thiazole, triazole and tetrazole and thiophene.
  • Suitable substituents for heteroaryl are described below in the definition of "optionally substituted”.
  • cyano refers to the group -CN.
  • acetyl refers to the group -C(O)R b , where R b is alkyl, cycloalkyl, or heterocyclyl, as each is defined herein.
  • spiro compound is meant a bicvclic organic compound with rings connected through just one atom.
  • the rings can be different in nature or identical.
  • the connecting atom is also called the spiroatom, most often a quaternary carbon ("spiro carbon").
  • All spiro compounds have the infix spiro followed by square brackets [] containing the number of atoms in the smaller ring and the number of atoms in the larger ring excluding the spiroatom itself.
  • compound A is called 1-bromo-3-chlorospiro[4.5]decan-7- o/
  • compound B is called 1-bromo-3-chlorospiro[3.6]decan-7-ol.
  • the spiro compound consisting of a cyclohexane ring and a cyclopentane ring is called spiro[4.5]decane.
  • the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.
  • the phrase “optionally substituted” or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substitutent group. The phrase should not be interpreted as duplicative of the substitutions herein described and depicted.
  • Exemplary optional substituent groups include acyl, alkyl, alkylsulfonyl, alkoxy, alkoxycarbonyl, cyano, halogen, haloalkyl, hydroxyl, oxo, and nitro.
  • the compounds of this invention may be made by a variety of methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention. Compounds of the invention can be readily prepared according to Schemes 1 and 2 by those skilled in the art. Pyridone intermediates of the invention can be prepared as illustrated in Scheme 1.
  • the invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula I or pharmaceutically acceptable salt, thereof and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts).
  • a pharmaceutical composition also referred to as pharmaceutical formulation
  • excipients also referred to as carriers and/or diluents in the pharmaceutical arts.
  • the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
  • a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula I or salt thereof with at least one excipient.
  • Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of Formula I or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
  • Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes.
  • Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).
  • pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • the compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica,
  • talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
  • the compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided.
  • Dyestuffs can be added to these coatings to distinguish different dosages.
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient.
  • Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
  • the term "treatment” includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
  • Prophylaxis or prevention or delay of disease onset is typically accomplished by administering a drug in the same or similar manner as one would to a patient with the developed disease or condition.
  • the present invention provides a method of treatment in a mammal, especially a human, suffering from obesity, diabetes, hypertension, depression, anxiety, drug addiction, substance addiction, or a combination thereof.
  • Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula I or salt thereof to said mammal, particularly a human.
  • Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula I or salt thereof to said mammal, particularly a human.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • therapeutically effective amounts of a compound of Formula I, as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
  • a therapeutically effective amount of a compound of Formula I or salt thereof may be administered as the raw chemical, it is typically presented as the active ingredient of a pharmaceutical composition or formulation.
  • a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian.
  • a compound of Formula I or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day.
  • Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula I per se. Similar dosages should be appropriate for treatment (including prophylaxis) of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.
  • the present invention comprises a compound of Formula I or salt thereof or a pharmaceutical composition thereof with at least one other anti-obesity drug and/or at least one anti-diabetes drug.
  • anti-obesity drugs can include, for example, Metformin (or glucophage), CB1 receptor antagonists, GLP-1 agonists, opioid antagonists, and neurotransmitter reuptake inhibitors.
  • a compound of the invention is employed in combination with another anti-obesity drug or anti-diabetes drug, it is to be appreciated by those skilled in the art that the dose of each compound or drug of the combination may differ from that when the drug or compound is used alone. Appropriate doses will be readily appreciated and determined by those skilled in the art.
  • the appropriate dose of the compound of Formula I or salt thereof and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are with the expertise and discretion of the attending doctor or clinician.
  • Step 1 ethyl 1-acetylcyclopropanecarboxylate
  • Step 3 (f?)-1-(2-methyl-1 ,3-dioxolan-2-yl)- ⁇ /-(1-phenylethyl)cyclopropane carboxamide
  • Step 4 (R)-I -(2-(bromomethyl)-1 ,3-dioxolan-2-yl)- ⁇ /-(1-phenylethyl) cyclopropanecarboxamide
  • Step 6 (f?)-5-(1-phenylethyl)-5-azaspiro[2.4]heptane-4,7-dione
  • Step 7 (f?)-7-(hydroxyimino)-5-(1-phenylethyl)-5-azaspiro[2.4]heptan-4-one
  • Step 8 7-amino-5-[(R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one
  • Step 9 tert-butyl ⁇ 4-oxo-5-[(R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-yl ⁇ carbamate
  • Step 11 tert-butyl methyl(5-[(f?)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-yl) carbamate
  • Example 1 4- ⁇ [(5-chloro-2-pyridinyl)methyl]oxy ⁇ -6'-(1-oxo-2,7-diazaspiro[4.5]decan-1-one- 7-yl)-2H-1 ,3'-bipyridin-2-one
  • Example 2 4- ⁇ [(5-chloro-2-pyridinyl)methyl]oxy ⁇ -6'-(2,7-diazaspiro[4.4]nonan-2-yl)-2/-/-1 ,3'- bipyridin-2-one
  • Example 3 4- ⁇ [(5-chloro-2-pyridinyl)methyl]oxy ⁇ -6'-(3,9-diazaspiro[5.5]undecane-2,4-dione-9-yl)-2/-/-1 ,3'- bipyridin-2-one
  • Example 4 4- ⁇ [(5-chloro-2-pyridinyl)methyl]oxy ⁇ -6'-(1-oxo-2,7-diazaspiro[3.5]nonan-2-yl)-2/-/- 1 ,3'-bipyridin-2-one
  • Examples 5-28 (RENUMBERED) of the Compounds of Formula I were prepared by the methods described above for Examples 1-4 (RENUMBERED), or routine variations thereof, starting from the requisite 6'-halopyridine and amine (or appropriately functional-group- protected version thereof, with subsequent routine deprotection).
  • the requisite amines (and appropriately functional-group-protected versions thereof) utilized herein were purchased if available commercially, were synthesized as described in the literature or by routine modifications thereof known by those skilled in the art, or were synthesized by alternative procedures known by those skilled in the art.
  • MCHR1 PlC ⁇ n Determination FLIPRTM Assay HEK293 cells stably transfected with hMCHRI were propagated as adherent cultures at 37 0 C in a humidified incubator. Cells were split 1 :8 at 90% confluency two times per week. New cell stocks were recovered from storage every two months. Cells were plated in black 384-well plates (Greiner) 24 hours prior to assay at 15,000 cells/well in 50 ⁇ l_ DMEM/F12, 10% FBS, 2 mM l-glutamine. Compounds to be profiled were prepared by making a stock solution at 3x10 "3 M in 100% DMSO. The stock solutions were serially diluted 1 :4 in 100% DMSO using JANUS
  • MCHR1 plCfin Determination Reporter Gene Assay The assay consists of cells plated at ten thousand cells/well in DMEM/F12, 5% FBS, 2 mM l-glutamine in black 384-well assay plates. The day after plating, the media was removed by aspiration seventeen hours prior to assay, followed by the addition of 50 ⁇ L of media without serum to reduce background signal noise. Compounds were prepared by making a stock solution at 3x10 "3 M. The stock solutions is serially diluted 1 :4 in 100% DMSO using the JANUS liquid handling instrument (Perkin Elmer) to allow for an 11 point curves in singlicate.
  • JANUS liquid handling instrument Perkin Elmer
  • the amount of luciferase generated was quantified in a TopCount (PerkinElmer Packard) at 19.8 0 C in SPC (single photon counting) mode with a 5 second count/well and subjected to a nonlinear regression analysis curve fitting program to generate plC 5 oS.
  • TopCount PerkinElmer Packard
  • SPC single photon counting
  • Exemplified compounds of the present invention were tested according to the above assays and were found to be functional antagonists of MCH at MCHR1.
  • the IC 50 S in the FLIPRTM assay ranged from about 10 nM to 0.5 uM. The majority of the compounds were ⁇ 60 nM; the most active compounds were ⁇ 40 nM.
  • Example 4 The compound of Example 4 was tested generally according to the assays described herein and in at least one experimental run exhibited an IC 50 value equal to 49 nM in the FLIPRTM assay.
  • Example 11 The compound of Example 11 was tested generally according to the assays described herein and in at least one experimental run exhibited an IC 50 value equal to 50 nM in the FLIPRTM assay.
  • Example 12 The compound of Example 12 was tested generally according to the assays described herein and in at least one experimental run exhibited anlC 50 value equal to 54 nM in the FLIPRTM assay.

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Abstract

L'invention concerne de nouvelles bis-pyridylpyridones qui sont des antagonistes de récepteur d'hormone concentrant la mélanine 1 (MCHR1 ), des compositions pharmaceutiques les contenant, des procédés pour les préparer, et leur utilisation en thérapie et pour le traitement de l'obésité et du diabète.
PCT/US2010/037017 2009-06-03 2010-06-02 Bis-pyridylpyridones à usage d'antagonistes de récepteur d'hormone concentrant la mélanine 1 WO2010141545A1 (fr)

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EP10783986A EP2437601A4 (fr) 2009-06-03 2010-06-02 Bis-pyridylpyridones à usage d'antagonistes de récepteur d'hormone concentrant la mélanine 1
JP2012514068A JP2012528872A (ja) 2009-06-03 2010-06-02 メラニン凝集ホルモン受容体１アンタゴニストとしてのビス−ピリジルピリドン類
US13/375,616 US20120071459A1 (en) 2009-06-03 2010-06-02 Bis-pyridylpyridones as melanin-concentrating hormone receptor 1 antagonists

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US20120077794A1 (en) * 2009-06-03 2012-03-29 Glaxsmithkline Llc Bis-pyridylpyridones as melanin-concentrating hormone receptor 1 antagonists
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
WO2015031036A1 (fr) * 2013-08-26 2015-03-05 Purdue Pharma L.P. Dérivés d'azaspiro[4.5] décane et leur utilisation
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US9365540B2 (en) 2012-01-12 2016-06-14 Takeda Pharmaceutical Company Limited Benzimidazole derivatives as MCH receptor antagonists
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones

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EP3556760A1 (fr) * 2018-04-19 2019-10-23 F. Hoffmann-La Roche AG Spirocomposés
CN112312904A (zh) 2018-04-16 2021-02-02 C4医药公司 螺环化合物

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WO2007141200A1 (fr) * 2006-06-02 2007-12-13 Janssen Pharmaceutica N.V. Nouveaux dérivés de pyridinone substituée par n-aryle et n-hétéroaryle en vue d'une utilisation dans des maladies à médiation par mch-1
US20080085884A1 (en) * 2006-10-06 2008-04-10 Pfizer Inc Melanin Concentrating Hormone Receptor-1 Antagonist Pyridinones

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US20070208046A1 (en) * 2004-03-05 2007-09-06 Norikazu Otake Pyridone derivative
WO2007141200A1 (fr) * 2006-06-02 2007-12-13 Janssen Pharmaceutica N.V. Nouveaux dérivés de pyridinone substituée par n-aryle et n-hétéroaryle en vue d'une utilisation dans des maladies à médiation par mch-1
US20080085884A1 (en) * 2006-10-06 2008-04-10 Pfizer Inc Melanin Concentrating Hormone Receptor-1 Antagonist Pyridinones

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE47142E1 (en) 2008-06-03 2018-11-27 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US9290450B2 (en) 2008-06-03 2016-03-22 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US8969347B2 (en) 2008-06-03 2015-03-03 Intermune, Inc. Compounds and methods for treating inflammatory and fibrotic disorders
US20120077794A1 (en) * 2009-06-03 2012-03-29 Glaxsmithkline Llc Bis-pyridylpyridones as melanin-concentrating hormone receptor 1 antagonists
US9365540B2 (en) 2012-01-12 2016-06-14 Takeda Pharmaceutical Company Limited Benzimidazole derivatives as MCH receptor antagonists
US10898474B2 (en) 2012-10-02 2021-01-26 Intermune, Inc. Anti-fibrotic pyridinones
US10376497B2 (en) 2012-10-02 2019-08-13 Intermune, Inc. Anti-fibrotic pyridinones
US9359379B2 (en) 2012-10-02 2016-06-07 Intermune, Inc. Anti-fibrotic pyridinones
US9675593B2 (en) 2012-10-02 2017-06-13 Intermune, Inc. Anti-fibrotic pyridinones
US9884865B2 (en) 2013-08-26 2018-02-06 Purdue Pharma L.P. Azaspiro[4.5] decane derivatives and use thereof
CN105612152A (zh) * 2013-08-26 2016-05-25 普渡制药公司 氮杂螺[4.5]癸烷衍生物及其用途
WO2015031036A1 (fr) * 2013-08-26 2015-03-05 Purdue Pharma L.P. Dérivés d'azaspiro[4.5] décane et leur utilisation
US11180502B2 (en) 2013-08-26 2021-11-23 Purdue Pharma L.P. Azaspiro[4.5]decane derivatives and use thereof
US10233195B2 (en) 2014-04-02 2019-03-19 Intermune, Inc. Anti-fibrotic pyridinones
US10544161B2 (en) 2014-04-02 2020-01-28 Intermune, Inc. Anti-fibrotic pyridinones

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